Collagen is a protein which is abundant in skin, blood vessels, cornea, tendons, bones and teeth of animals, and which has a molecular weight of about 300,000. Collagen can be described as having a rod-like molecular structure of helical configuration consisting of three polypeptide chains, about 3,000 .ANG. in length and about 15 .ANG. in diameter.
Collagen is widely used in medical treatments. Purified collagen is used as local hemostatics, artificial skin, artificial eardrums, and contact lenses.
Collagen can also be injected into a living body for filling voids or depressions in defective tissues resulting from traffic accidents and operations, so that reparation of the tissues by fibroblasts is promoted. Conventionally, such an internally injected collagen comprises only collagen, such as an aqueous solution type (JP-B-62-37020) (the term "JP-B" as used herein means an examined Japanese Patent Publication), an aqueous dispersion of regenerated collagen fibers, and an aqueous dispersion of regenerated collagen fibers which have been crosslinked with a crosslinking agent (JP-A-58-170796, Japanese Patent Application No. 61-273156) (the term "JP-A" as used herein means an unexamined published Japanese Patent Application).
Specific examples include Koken Atelocollagen Implant (manufactured by Koken, Japan) as an aqueous solution type, Zyderm I and II (manufactured by Collagen Corp., U.S.A.) as a regenerated collagen fiber type, and Zyplast (manufactured by Collagen Corp., U.S.A.) as a crosslinked collagen type. The aqueous solution of collagen has an excellent fluidity through an injection needle, but it is easily absorbed into a living body. Thus, it has a problem with respect to antigenicity. Namely, an intracutaneous test observed 2 to 3% of subjects showing a response or reaction after injection, and a continued injection revealed additional 2 to 3% of subjects showing a response or reaction. Further, the required repetition of injection is necessary for maintaining an upheaval effect on skin. The upheaval effect of the skin can be described as the raising of the skin above the depression which is caused by injecting the aqueous solution of collagen into the depression underneath the skin. In other words, after injection of the aqueous solution of collagen into the depression, the skin is raised above the depression, so as to form a smooth level surface with the surrounding skin.
The crosslinked collagen can be made so that its absorption into a living body is reduced. Therefore, it has some advantages with respect to inhibition of antigenicity and maintenance of the upheaval effect on the skin. However, it has the problem that the addition of the residual crosslinking agent increases toxicity. Also, it has a fluidity inferior to that of the aqueous solution type and cannot be injected as smoothly as the aqueous solution type.
The properties of the regenerated fiber type collagen is positioned between those of the aqueous solution type and the crosslinked fiber type, and thus has both similar advantages and disadvantages. However, it is more easily absorbed into the body than the crosslinked collagen.
Hyaluronic acid is a component present in any part of a living body and is one of the substances called mucopolysaccharides. It is a very large, straight chain polymer having a molecular weight of from the hundreds thousands to millions. Hyaluronic acid consists of the chain of recurring disaccharide units in which N-acetylglucosamine and glucuronic acid are bonded together. Unlike the other mucopolysaccharides, it is free of a sulfate group and is believed to have the simplest structure of the mucopolysaccharides.
An aqueous solution of hyaluronic acid has a very characteristic viscoelastic property and a remarkably high water holding capacity, and it is in the form of viscous gel even in a dilute solution. Hyaluronic acid is one of the substrate components common to any connective tissues and hence has a function of holding water within the intercellular spaces.
It is known that hyaluronic acid forms a jelly-like matrix in the tissue to hold the cells and suppress the transfer of intercellular substances. This also protects against mechanical shocks and bacterial infection from the outside. The specific water holding capacity of hyaluronic acid is believed to be caused by the entanglement phenomenon that hyaluronic acid forms a continuous polymeric network in which individual molecules cannot be distinguished.
In the past, various attempts have been made to use these properties of hyaluronic acid for medical treatment. For example, hyaluronic acid has been used in treating agents for arthritic diseases, as vitreous replacements, and covering agents for skin wounds.
A specific aqueous collagen solution containing hyaluronic acid is described in Jinko Zoki (Japan J. Artificial Organs) 12(1), 327-220 (1983).